Search

BACKGROUND: Effective biomarkers for prediction of recurrence of lung adenocarcinoma cancer (LADC) patients are needed to determine treatment strategies post-surgery to improve outcome. OBJECTIVE: This study evaluates the efficacy of carboxypeptidase E (CPE) mRNA including its splice isoforms, CPE-ΔN, as a biomarker for predicting recurrence in adenocarcinoma patients. METHODS: RNA was extracted from resected tumors from 86 patients with different stages of non-small cell LADC. cDNA was synthesized and qRT-PCR carried out to determine the copy numbers of CPE/CPE-ΔN mRNA. Patients were followed for 7 years post-tumor resection to determine recurrence and death. RESULTS: ROC curve analysis showed the overall AUC for CPE/CPE-ΔN copy number was 0.563 in predicting recurrence and 0.562 in predicting death. Kaplan-Meier survival analysis showed statistical difference (p= 0.018), indicating that patients with high CPE/CPE-ΔN copy numbers had a shorter time of disease-free survival and also shorter time to death (p= 0.035). Subgroup analyses showed that association of disease-free survival time with CPE/CPE-ΔN copy number was stronger among stage I and II LADC patients (p= 0.047). CONCLUSIONS: CPE/CPE-ΔN mRNA is a potentially useful biomarker for predicting recurrence and death in LADC patients, especially in identifying patients at high risk of recurrence at early stages I and II.

Hepatocellular carcinoma (HCC) is a cancer with relatively high mortality, yet little attention has been devoted for related prognostic biomarkers. This study analyzed differential expression of m5C RNA methyltransferase-related genes in normal samples and tumors samples in TCGA-LIHC using Wilcoxon test. K-means consensus clustering analysis was implemented to subdivide samples. Independent prognostic factors were screened by univariate and multivariate Cox regression analyses. KEGG pathway enrichment analysis was performed on the screened independent prognostic factor using GSEA tools. qPCR was conducted to test mRNA expression of key m5C RNA methyltransferase-related genes in tissues and cells. There were 7 m5C RNA methyltransferase-related genes (NOP2, NSUN4, etc.) differentially expressed in HCC tumor tissues. HCC samples were classified into 3 subgroups through clustering analysis according to the expression mode of m5C RNA methyltransferase-related genes. It was also discovered that patients in different subgroups presented significant differences in survival rate and distribution of grade. Additionally, NOP2, NSUN4 and NSUN5 expression notable varied in different grades. Through regression analyses combined with various clinical pathological factors, it was displayed that NSUN4 could work as an independent prognostic factor. KEGG analysis showed that NSUN4 mainly enriched in signaling pathways involved in ADHERENS JUNCTION, RNA DEGRADATION, MTOR SIGNALING PATHWAY, COMPLEMENT and COAGULATION CASCADES. As examined by qPCR, NSUN4 was conspicuously upregulated in HCC patient’s tissues and cells. Altogether, our study preliminarily developed a novel biomarker that could be independently used in prognosis of HCC, which may provide a new direction for the study of related molecular mechanism or treatment regimen.

Early tumor size reduction (TSR) has been explored as a prognostic factor for survival in patients with advanced melanoma in clinical trials. The purpose of this analysis is to validate, in a routine clinical milieu, the predictive capacity of TSR by 10% for overall survival (OS) and progression-free survival (PFS) and to compare its predictive performance with the RECIST 1.1 criteria.This retrospective study was approved by the local ethics committee. A total of 152 patients with both CT before immunotherapy initiation and at first response evaluation after immunotherapy initiation were included. Prior to statistical analysis, treatment response was trichotomized as follows: Complete response and/or partial response, stable disease and progressive disease. Furthermore, response was dichotomized regarding TSR (TSR ≥ 10% and TSR10%). Kaplan-Meier survival estimates, Cox regression and Harrel's concordance index (C-index) were computed for prediction of overall survival and progression-free survival.Tumor size reduction by at least 10% significantly differentiated between patients with increased survival from the ones with decreased survival (median OS: TSR ≥ 10%: 2137 days vs. TSR10%: 263 days) (p0.001) (median PFS: TSR ≥ 10%: 590 days vs. TSR10%: 11 days) (p0.001). RECIST 1.1. criteria had a slightly higher C-index for overall survival reflecting a slight superior predictive capacity (RECIST: 0.69 vs TSR: 0.64) but a similar predictive capacity regarding progression-free survival (both: 0. 63).Early tumor size reduction serves as a simple-to-use metric which can be implemented on the first follow-up CT. Tumor size reduction by at least 10% can be considered an additional biomarker predictive of overall survival and progression-free survival in routine clinical care and not only in the context of clinical trials in patients with advanced melanoma undergoing immunotherapy. Nevertheless, RECIST-based criteria should remain the main tool of treatment response assessment until results of prospective studies validating the TSR method are available.

Background and aims White blood cell (WBC) count is an easily obtainable biomarker of systematic inflammation. Our study aimed to investigate the associations of differential WBC count with all-cause and cause-specific mortality in a general Asian population. Methods and Results Cox proportional hazards model was used to evaluate the associations of WBC count with mortality separately for men and women, with adjustment for multiple variables including age, smoking, and other lifestyle factors. Stratified analyses by age, smoking, diabetes, and hypertension were conducted to explore potential effect modification. Elevated WBC count was significantly associated with increased mortality risk. The adjusted hazard ratios of total WBC (10th decile compared to decile of lowest risk) for all-cause mortality were 1.42 (95% CI: 1.33, 1.53) for men and 1.54 (95% CI: 1.42, 1.68) for women. Similar risks were observed for neutrophils, monocytes, and neutrophil/lymphocyte (NL) ratio. The highest deciles of neutrophils, monocytes, and NL ratio were also positively associated with risk of cardiovascular/cerebrovascular, cancer, and respiratory mortality after adjusting for covariates. Results for all-cause mortality remained statistically significant for participants who were Conclusions Total and differential WBC counts (neutrophils, monocytes, and NL ratios) are positively associated with increased risk of all-cause mortality, cardiovascular and cerebrovascular, cancer, and respiratory mortality among Taiwanese adults.

BACKGROUND/PURPOSE Klebsiella pneumoniae bacteremia-induced sepsis is a clinically important condition with a high mortality rate and various known virulence factors. However, studies on the association of these virulence factors with the occurrence of K. pneumoniae bacteremia-induced sepsis are scarce. We aimed to investigate clinical variables and virulence factors in patients with K. pneumoniae bacteremia-induced sepsis. METHODS We retrospectively reviewed the medical records of 76 patients with K. pneumoniae bacteremia between January 2012 and July 2017. Patients were divided into sepsis (n = 25) and non-sepsis (n = 51) groups. Patient background characteristics, antimicrobial regimens, and prognosis were evaluated. We assessed the distribution of virulence factors related to K. pneumoniae, such as mucoviscosity, capsular polysaccharide, and siderophores. Siderophore production levels were determined by measuring the orange halo zone on chrome azurol S agar plate assay. RESULTS There were no intergroup differences in male-to-female ratio and age. Multivariable analysis revealed that siderophore production level (p

Bipolar androgen therapy (BAT) is a novel treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively identified patients with mCRPC that achieved deep PSA responses to BAT. All patients with available next-generation molecular sequencing harbored pathogenic mutations in TP53 and/or a homologous recombination DNA repair gene. BACKGROUND: Bipolar androgen therapy (BAT) is an emerging treatment strategy for men with metastatic castration resistant prostate cancer (mCRPC) whereby serum testosterone is cycled from supraphysiologic to near-castrate levels each month. BAT has been shown to induce clinical responses in a significant proportion of patients, some of which are extreme. We explored the clinical and molecular characteristics of patients with mCRPC who achieved deep responses to BAT. METHODS: We conducted a retrospective analysis of patients with mCRPC treated with BAT at Johns Hopkins. We identified 22 of 114 (19%) patients with mCRPC who achieved ≥70% PSA reductions upon treatment with BAT. All patients were treated using 400 mg testosterone cypionate intramuscularly every 28 days, together with continuous LHRH agonist therapy. Clinical-grade DNA sequencing was obtained using commercially available assays. RESULTS: Somatic next-generation sequencing was obtained for 15 of 22 (68%) patients. Of these 15 extreme PSA responders with sequencing data available, All 15 of 15 (100%) harbored a pathogenic mutation in TP53 and/or a homologous recombination DNA repair (HRD) gene. Among the subset of patients with measureable disease (N = 15), 10 patients (67%) achieved an objective response including one patient with a complete response. The median radiographic progression-free survival of these deep PSA responders was 11.3 months (95% CI, 7.9–25.0 months). CONCLUSIONS: We observed an enrichment of TP53 and HRD mutations in mCRPC patients with extreme PSA responses to BAT, with durability lasting about a year. These data support the hypothesis that BAT may most benefit patients with DNA repair-deficient mCRPC. Further studies of BAT in biomarker-selected mCRPC populations (ie, TP53/HRD-mutated) are warranted.

Background CDK4/6 inhibitors have been used to treat hormone receptor-positive HER2-negative advanced breast cancer. Their benefit in HER2-positive breast cancer has not been determined yet. In this study, we investigated the effects of HER2 on CDK4/6 activity by assessing the level of downstream phosphorylated retinoblastoma protein (pRb) in HER2-positive breast cancer (HER2 positivity is defined by immunohistochemical study or FISH, regardless of ER status) to determine if these cases may be responsive to CDK4/6 inhibitors. Materials and Methods One hundred and thirty cases of breast biopsies with invasive carcinoma were collected, including 77 cases of HER2+ (39 cases of ER +PR±HER2+ and 38 cases of ER-PR-HER2+) and 53 cases of HER2- (ER-PR-HER2-) breast cancer. Immunohistochemical study of pRb was performed and the pRb level was assessed by H-score (intensity x percentage of positive cells). Results The pRb H-score ranges from 3 to 270. The average H-scores for the ER-PR-HER2+, ER+PR±HER2+ and ER-PR-HER2- groups are 115.8 ± 75.8, 93.1 ± 68.6 and 63.1 ± 65.6, respectively. By comparison, HER2+ cases have significantly higher pRb levels than HER2- cases (P = .001). Among HER2+ cases, there was a trend of positive correlation between the HER2 gene copy number, and the pRb level although not statistically significant (r = 0.192, 95% CI, [-0.033, 0.399], P = .09). Conclusion In breast cancer, HER2 positivity leads to significantly higher levels of CDK4/6 activity as reflexed by pRb. Breast cancer that is positive for HER2 may respond to CDK4/6 inhibitors and pRb may potentially be used as a biomarker to predict the responsiveness.

Objectives The association of dialysis fistulas and heart failure is believed to be due to high cardiac output. N-terminal pro-B-Type Natriuretic Peptide (pro-BNP) which is secreted by the cardiac ventricles in response to excessive stretching of the myocytes has been used as a marker of heart failure with 90% sensitivity. We report our early experience using pro-BNP levels to test the efficacy of the novel ‘secondary extension technique’ (SET) in improving myocardial function by reducing fistula flow. Methods 11 patients with high fistula flows (>3000ml/m, all brachio-cephalic) and raised pro-BNP underwent SET between 2011 and 2015. SET involves extending the anastomosis from brachial to either proximal radial or ulnar arteries. We measured pro-BNP levels, fistula flow and clinical improvements both pre and post operatively. Results SET resulted in a median (IQR) flow rate decrease of 57.9 (11.9) % which correlated with a fall in pro-BNP of 69.6 (39) %. 7 of the 11 patients in the series pro-BNP level returned to a normal value at average follow-up of 3 months post SET. All patients had HOF-related symptom resolution post-procedure and remained asymptomatic at last follow-up Conclusion Our pilot data suggests that SET is an effective way of reducing fistula flow. It also shows that BNP may be a reliable biomarker in assessing the impact of the technique on cardiac function. These results warrant further investigation in the form of a definitive, multicentre study.

To investigate, by means of spectral domain optical coherence tomography, retinal reflectivity changes as an early biomarker anticipating radiation-induced macular edema (ME) in patients treated by iodine-125 (I-125) brachytherapy.Thirty patients planned for I-125 brachytherapy because of uveal melanoma were prospectively included and followed every 4 months for five years. Reflectivity alterations, namely hyperreflective retinal foci, were characterized and counted by two independent masked examiners by means of spectral domain optical coherence tomography imaging. Hyperreflective retinal foci were defined as discrete intraretinal reflectivity changes ≤30 µm, with reflectivity similar to nerve fiber layer and without back shadowing.Macular edema occurred in 17 patients (24.2 ±15.1 months) (group 1) after irradiation. Thirteen patients showed no signs of ME at the 5-year follow-up (group 2). The number of hyperreflective retinal foci was statistically higher in sequential visits until the evidence of ME in group 1 vs group 2 (P0.0001). In group 1, hyperreflective retinal foci at the follow-up before the evidence of ME were significantly related to the OCT central subfield thickness at ME appearance (P = 0.0002, r2=0.6129). The intergrader agreement was almost perfect (intraclass correlation coefficient = 0.80).Hyperreflective retinal foci may be considered as an early in vivo imaging biomarker of retinal inflammatory response to ocular irradiation, anticipating the development of radiation maculopathy.

Aims: Given the reversibility of methylation, biomarkers with discriminating ability are of great interest for targeted therapeutic sites. Materials & methods: Methylation array data of 461 lung adenocarcinoma (LUAD) patients comprising of 458 tumor and 32 LUAD paracancerous samples were compared using partial least squares discrimination analysis and receiver operating characteristics analysis. Results: A six-DNA methylation signature (corresponding to five genes) was found to significantly discriminate normal and LUAD samples. Kyoto Encyclopedia of Genes and Genomes analysis indicated enrichment of methylation sites in the Wnt pathway in LUAD compared with controls. Conclusion: This six-DNA methylation signature demonstrated potential as a novel biomarker for diagnosis and therapeutic targets. Further, inhibition of Wnt signaling pathway may be an important step in LUAD progression.

Background Inappropriate and excessive activation of type I interferon (IFN) system is a key feature of systemic lupus erythematosus (SLE), and its targeting has led to important achievements in the development of novel drugs for SLE. Aim of the work To evaluate the serum levels of interferon lambda IFNλ3 (IL28B) in Egyptian patients with SLE and investigate its potential relation with different clinical and laboratory parameters. Patients and methods The study included 40 SLE patients and 40 controls. The SLE disease activity index (SLEDAI) was assessed. The measurement of serum levels of IFNλ3 was performed in all participants using enzyme linked immunosorbent assay (ELISA). Results The mean age of the patients was 26.8 ± 7.8 years with disease duration 5.1 ± 4.5 years and they were 35 females and 5 males. The serum levels of IFNλ3 were significantly higher in SLE patients (9.7 ± 12.47 pg/mL) compared to the control (5.13 ± 1.63 pg/mL)(p = 0.02). Significant correlations were observed between serum IFNλ3 and serositis (r = 0.35,p = 0.03), C3 consumption (r −0.33, p = 0.04) and SLEDAI (r 0.34, p = 0.03). On multivariate regression analysis, serositis and SLEDAI (but not C3) were significant independent predictors of IFNλ3 levels (β = 0.08, p = 0.037 and β = 0.06, p = 0.014 respectively). Conclusion The results support a possible role of IFNλ3/IL28B in the immunopathogenesis of SLE. The significant association of serum IFNλ3 with disease activity highlights the utility of IFNλ3 as a novel biomarker for monitoring disease activity and predicting severity in SLE. Further studies on IFNλ3 in SLE could be promising in the development of personalized therapy for lupus patients.

Carotid intima media thickness (cIMT) is a biomarker of subclinical atherosclerosis and a predictor of future cardiovascular events. Identifying associations between gene expression levels and cIMT may provide insight to atherosclerosis etiology. Here, we use two approaches to identify associations between mRNA levels and cIMT: differential gene expression analysis in whole blood and S-PrediXcan. We used microarrays to measure genome-wide whole blood mRNA levels of 5647 European individuals from four studies. We examined the association of mRNA levels with cIMT adjusted for various potential confounders. Significant associations were tested for replication in three studies totaling 3943 participants. Next, we applied S-PrediXcan to summary statistics from a cIMT genome-wide association study (GWAS) of 71 128 individuals to estimate the association between genetically determined mRNA levels and cIMT and replicated these analyses using S-PrediXcan on an independent GWAS on cIMT that included 22 179 individuals from the UK Biobank. mRNA levels of TNFAIP3, CEBPD and METRNL were inversely associated with cIMT, but these associations were not significant in the replication analysis. S-PrediXcan identified associations between cIMT and genetically determined mRNA levels for 36 genes, of which six were significant in the replication analysis, including TLN2, which had not been previously reported for cIMT. There was weak correlation between our results using differential gene expression analysis and S-PrediXcan. Differential expression analysis and S-PrediXcan represent complementary approaches for the discovery of associations between phenotypes and gene expression. Using these approaches, we prioritize TNFAIP3, CEBPD, METRNL and TLN2 as new candidate genes whose differential expression might modulate cIMT.

As the most common cause of dementia, the study of Alzheimer’s disease (AD) faces challenges in terms of understanding the cause, monitoring the pathogenesis, and developing early diagnosis and effective treatment. Rapid and accurate identification of AD biomarkers in the brain is critical to provide key insights into AD and facilitate the development of early diagnosis methods. In this work, we developed a platform that enables a rapid screening of AD biomarkers by employing graphene-assisted Raman spectroscopy and machine learning interpretation in AD transgenic animal brains. Specifically, we collected Raman spectra on slices of mouse brains with and without AD and used machine learning to classify AD and non-AD spectra. By contacting monolayer graphene with the brain slices, the accuracy was significantly increased from 77% to 98% in machine learning classification. Further, using linear supporting vector machine (SVM), we identified a spectral feature importance map that reveals the importance of each Raman wavenumber in classifying AD and non-AD spectra. Based on this spectral feature importance map, we identified AD biomarkers including Aβ and tau proteins, and other potential biomarkers, such as triolein, phosphatidylcholine, and actin, which have been confirmed by other biochemical studies. Our Raman-machine learning integrated method with interpretability is promising to greatly accelerate the study of AD and can be extended to other tissues, biofluids, and for various other diseases.

Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.

Colorectal cancer is the 3rd most commonly diagnosed cancer, with rectal cancer accounting for 30% of cases. The current standard of care curative treatment for locally advanced rectal cancer is (chemo)radiotherapy followed by surgery and adjuvant chemotherapy. Although neoadjuvant radiotherapy has reduced the risk of local recurrence to less than 10%, the risk of distant metastasis remained high at 30% affecting patient survival. In addition, there is a recognition that there is heterogeneity in tumour biology and treatment response with good responders potentially suitable for treatment de-escalation. Therefore, new treatment sequencing and regimens were investigated. Here, we reviewed the evidence for current neoadjuvant treatment options in patients with locally advanced rectal adenocarcinoma, and highlight the new challenges in this new treatment landscape.

In the past decade, there has been an increasing awareness that traumatic brain injury (TBI) and concussion substantially increase the risk for developing psychiatric disorders. Even mild TBI increases the risk for depression and anxiety disorders such as posttraumatic stress disorder by two- to threefold, predisposing patients to further functional impairment. This strong epidemiological link supports examination of potential mechanisms driving neuropsychiatric symptom development after TBI. One potential mechanism for increased neuropsychiatric symptoms after TBI is via inflammatory processes, as central nervous system inflammation can last years after initial injury. There is emerging preliminary evidence that TBI patients with posttraumatic stress disorder or depression exhibit increased central and peripheral inflammatory markers compared with TBI patients without these comorbidities. Growing evidence has demonstrated that immune signaling in animals plays an integral role in depressive- and anxiety-like behaviors after severe stress or brain injury. In this review, we will 1) discuss current evidence for chronic inflammation after TBI in the development of neuropsychiatric symptoms, 2) highlight potential microglial activation and cytokine signaling contributions, and 3) discuss potential promise and pitfalls for immune-targeted interventions and biomarker strategies to identify and treat TBI patients with immune-related neuropsychiatric symptoms.

We systemically identified tuberculosis (TB)-related DNA methylation biomarkers and further constructed classifiers for TB diagnosis. TB-related DNA methylation datasets were searched through October 3, 2020. Limma and DMRcate were employed to identify differentially methylated probes (DMPs) and regions (DMRs). Machine learning methods were used to construct classifiers. The performance of the classifiers was evaluated in discovery datasets and a prospective independent cohort. Eighty-nine DMPs and 24 DMRs were identified based on 67 TB patients and 45 healthy controls from 4 datasets. Nine and three DMRs were selected by elastic net regression and logistic regression, respectively. Among the selected DMRs, two regions (chr3: 195635643–195636243 and chr6: 29691631–29692475) were differentially methylated in the independent cohort (p = 4.19 × 10−5 and 0.024, respectively). Among the ten classifiers, the 3-DMR logistic regression classifier exhibited the strongest performance. The sensitivity, specificity, and area under the curve were, respectively, 79.1%, 84.4%, and 0.888 in the discovery datasets and 64.5%, 90.3%, and 0.838 in the independent cohort. The differential diagnostic ability of this classifier was also assessed. Collectively, these data showed that DNA methylation might be a promising TB diagnostic biomarker. The 3-DMR logistic regression classifier is a potential clinical tool for TB diagnosis, and further validation is needed., Graphical abstract, We systemically identified TB-related DNA methylation biomarkers and constructed diagnostic classifiers. A 3-DMR logistic regression classifier showed excellent performance in discovery datasets and a prospective cohort. DNA methylation might be a promising TB-related biomarker and the 3-DMR logistic regression classifier is a potential clinical tool for TB diagnosis.

Background Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. Methods All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. Results Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4–9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. Conclusions Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers.

Background Non-invasive clinical algorithms for the detection of liver fibrosis (LF) can reduce the need for liver biopsy (LB). We explored the implementation of two serum biomarkers, enhanced liver fibrosis (ELF) and Mac-2 binding protein glycosylation isomer (M2BPGi), in clinical algorithms for LF in chronic hepatitis B (CHB) patients. Methods Two clinical algorithms were applied to 152 CHB patients: (1) transient elastography (TE) followed by biomarkers (TE/ELF and TE/M2GPGi); (2) biomarker test followed by TE (ELF/TE and M2BPGi/TE). Using the cut-off value or index for the detection of advanced LF (TE≥F3; 9.8 in ELF and 3.0 in M2BPGi), LB was expected to be performed in cases with discordant TE and biomarker results. Results In both algorithms, the expected number of LBs was lower when using M2BPGi than when using ELF (TE/ELF or ELF/TE, 13.2% [N=20]; TE/M2BPGi or M2BPGi/TE, 9.9% [N=15]), although there was no statistical difference (P=0.398). In the TE low-risk group (TE≤F2), the discordance rate was significantly lower in the TE/M2BPGi approach than in the TE/ELF approach (1.5% [2/136] vs. 11.0% [15/136], P=0.002). In the biomarker low-risk group, there was no significant difference between the ELF/TE and M2BPGi/TE approaches (3.9% [5/126] vs. 8.8% [13/147], P=0.118). Conclusions Both ELF and M2BPGi can be implemented in non-invasive clinical algorithms for assessing LF in CHB patients. Given the lowest possibility of losing advanced LF cases in the low-risk group when using the TE/M2BPGi approach, this combination seems useful in clinical practice.

Research question: Do women with laparoscopically confirmed endometriosis have higher plasma concentrations of circulating cell-free DNA (cirDNA) than those without endometriosis? Design: This prospective study recruited women aged 18-45 years undergoing benign gynaecological laparoscopy at two tertiary hospitals. Venous blood was collected immediately prior to surgery, and women were allocated to the endometriosis or control groups based on surgical findings. Total plasma cirDNA and cirDNA integrity were measured by qPCR targeting short (115 bases) and long (247 bases) ALU segments, while endometrial-derived cirDNA was measured by qPCR of bisulfite treated cirDNA using primers selective for a FAM101A sequence uniquely unmethylated in endometrial tissue. Five cirDNA parameters were compared between the control and endometriosis cohorts: total cirDNA concentration, long-stranded cirDNA concentration, integrity ratio, endometrial cirDNA concentration and endometrial cirDNA proportion. Results: Twenty-eight endometriosis and 15 control samples were included in analysis. Women with and without endometriosis had cirDNA concentrations of 2.24 ± 0.89 ng/mL and 2.56 ± 0.92 ng/mL respectively. Analysis by phenotype of endometriosis revealed a significantly higher endometrial cirDNA concentration in women with superficial disease (n = 10) compared to deep endometriosis (n = 18) (mean difference 0.14 ng/mL; 95% confidence interval 0.15-0.26; p = 0.025), but not compared to controls. Conclusions: There were no significant differences in any of the cirDNA parameters between women with and without endometriosis. The low statistical power and heterogenous pelvic pathology in the control group render it difficult to determine whether the negative results demonstrated in this study reflect a true lack of increase in cirDNA in endometriosis.

Considerable advancements have been made in the quantification of biofluid-based biomarkers for traumatic brain injury (TBI), which provide a clinically accessible window to investigate disease mechanisms and progression. Methods with improved analytical sensitivity compared with standard immunoassays are increasingly used, and blood tests are being used in the diagnosis, monitoring, and outcome prediction of TBI. Most work to date has focused on acute TBI diagnostics, while the literature on biomarkers for long-term sequelae is relatively scarce. In this review, we give an update on the latest developments in biofluid-based biomarker research in TBI and discuss how acute and prolonged biomarker changes can be used to detect and quantify brain injury and predict clinical outcome and neuropsychiatric sequelae.

Circulating tumour cells (CTCs) are cancer cells released by cancer into the peripheral circulation. Haematogenous tumour spread is a hallmark of metastatic malignancy and a key factor in cancer recurrence and prognosis. CTCs have diagnostic and prognostic significance for a number of adenocarcinomas and melanoma. A review of the published peer-reviewed literature was performed to determine the clinical relevance of CTCs as a biomarker in the management of oral squamous cell carcinoma (OSCC). Fourteen studies met the eligibility criteria. With regard to patients with OSCC, this review found the following: (1) CTCs have been detected using multiple techniques; (2) the presence of CTCs does not appear to be related to tumour differentiation or size; (3) CTCs may be detected without lymph node involvement; (4) the detection of CTCs may be prognostic for both disease-free survival and overall survival; (5) quantification of CTCs may reflect the efficacy of therapy; (6) CTCs may be of value for ongoing patient monitoring. Preliminary evidence suggests that CTCs have diagnostic and prognostic potential as a biomarker for oral cancer management and warrant further investigation to determine their appropriate place in the management of OSCC patients.

Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability.All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients.The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P.001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve,0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices.The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.

BACKGROUND The neutrophil to lymphocyte ratio (NLR) has been reported to be associated with clinical outcomes of patients with severe traumatic brain injury (TBI). This study aimed to evaluate the correlation between the dynamics of NLR and clinical outcomes of pediatric patients with moderate to severe TBI. METHODS We retrospectively evaluated the clinical data of a total of 374 pediatric patients with moder-ate to severe TBI who were treated in our department between May 2016 and May 2020. Clinical and laboratory data including the NLR upon admission and the NLR on hospital day four were collected. Poor clinical outcome was defined as Glasgow Outcome Scale (GOS) of 1-3. Multivariable logistic regression analyses were performed to investigate the correlation between the dynamics of NLR and clinical outcome. RESULTS Three hundred seventy-four pediatric patients (mean age 7.37 ± 3.11, 52.7% male) were evaluated. Based on the ROC curves, a value of 5 was determined as the NLR cut-off value. The corresponding cutoff value for delta NLR was 1. The Glasgow Coma Scale (GCS) (OR, 3.42; 95% CI: 1.88-5.28; P

Background Urine tissue inhibitor of metalloproteinases-2/insulin-like growth factor-binding protein 7 (TIMP-2/IGFBP7) (NephroCheck, Ortho Clinical Diagnostics, Raritan, NJ, USA) is a US Food and Drug Administration-approved biomarker for risk assessment of acute kidney injury (AKI) in critically ill adult patients in intensive care units; however, its clinical impact in the emergency department (ED) remains unproven. We evaluated the utility of NephroCheck for predicting AKI development and short-term mortality in the ED. Methods This was a prospective, observational, five-center international study. We consecutively enrolled ED patients admitted with ≥30% risk of AKI development (assessed by ED physician: ED score) or acute diseases. Serum creatinine was tested on ED arrival (T0), day 1, and day 2 (T48); urine for NephroCheck was collected at T0 and T48. We performed ROC curve and reclassification analyses. Results Among the 529 patients enrolled (213 females; median age, 65 years), AKI developed in 59 (11.2%) patients. The T0 NephroCheck value was higher in the AKI group than in the non-AKI group (median 0.77 vs. 0.29 (ng/m)2/1,000, P=0.001), and better predicted AKI development than the ED score (area under the curve [AUC], 0.64 vs. 0.53; P=0.04). In reclassification analyses, adding NephroCheck to the ED score improved the prediction of AKI development (P Conclusions NephroCheck can predict both AKI development and short-term mortality in at-risk ED patients. NephroCheck would be a useful biomarker for early ruling-in or ruling-out of AKI in the ED.

BACKGROUND: Interest in therapeutic applications of exogenous ketones has grown significantly, spanning patients with heart failure to endurance athletes. Exogenous ketones engender significant effects on cardiac function in heart failure and provide an ergogenic benefit in athletes. The aim of this study was to assess the effects of exogenous ketones on cardiac function in healthy participants. METHODS: In a single-arm intervention study, 20 fasting, healthy participants underwent comprehensive echocardiography (two-dimensional, Doppler, and strain) before and 30 min after weight-based oral ketone ester administration. The relationship between changes in log-transformed biomarker levels and change in absolute global longitudinal strain (GLS) was assessed using linear regression. RESULTS: The mean age was 30 ± 7 years, 50% were women, 45% were nonwhite, and the average body mass index was 24.3 ± 3.1 kg/m(2). Ketone ingestion acutely elevated β-hydroxybutyrate levels from a median of 0.13 mmol/L (interquartile range, 0.10–0.37 mmol/L) to 3.23 mmol/L (interquartile range, 2.40–4.97 mmol/L) (P < .001). After ketone ester consumption, systolic blood pressure, heart rate, biventricular function, left ventricular GLS, and left atrial (LA) strain all augmented, while systemic vascular resistance decreased. Displayed as mean change, increases in ejection fraction (3.1%; 95% CI, 2.0%−4.2%; P < .001), GLS (2.0%; 95% CI, 1.4%−2.7%; P < .001), right ventricular S′ (1.1 cm/sec; 95% CI, 0.4–1.8 cm/sec; P = .004), LA reservoir strain (7%; 95% CI, 3%−12%; P = .005), and LA contractile strain (4%; 2%−6%; P = .001) were observed. During robustly achieved ketosis, change in GLS was inversely associated with change in nonesterified fatty acids (P = .019). CONCLUSIONS: In a single-arm study, systolic blood pressure, heart rate, biventricular function, and LV and LA strain acutely augmented after ketone ester ingestion in healthy, fasting participants, similar to several effects observed in the failing heart. These data may provide supporting data for the ergogenic benefits observed in athletes and may become increasingly relevant with exogenous ketone consumption across a variety of cardiovascular and noncardiovascular applications.

Introduction Traumatic injury elicits an inflammatory response such as the one occurring during systemic infection. Monocyte distribution width (MDW) has been found to distinguish sepsis in a pool of patients with suspected infection. We hypothesized that an elevated MDW in trauma patients would be associated with the development of multiple organ dysfunction syndrome (MODS) and an increased mortality. Materials and Methods Observational study in a dedicated trauma Intensive Care Unit (ICU) in Madrid during 2019-2020. Patients were classified according to their first MDW value on admission, as greater or lesser than 21 U. Clinical data was obtained and univariate and multivariate analysis were realized, as well as a test performance analysis. Results 354 patients were studied, with a median age of 46 years, 78% male. Half presented with severe trauma ISS > 15, mostly with a blunt mechanism of injury. A MDW ≥ 21 U on admission was found in 17% of cases. These patients were more likely to present with hemodynamic instability and MODS. They had a higher length of stay (3.8 vs 2 days) and higher mortality (21 vs 5%) compared to the low MDW group. These findings remained statistically significant in the multivariate analysis, with an OR 4.6 (IC 95% 1.7-12) for MODS and 3.1 (IC 95% 1.2-8.3) for mortality. Conclusions In trauma patients, a MDW ≥ 21 U on admission was independently associated with a greater risk of MODS, a higher mortality and a higher length of stay. This biomarker could be useful in predicting severity in the initial evaluation of trauma patients.

Background The neutrophil-to-lymphocyte ratio (NLR) is a known prognostic biomarker for survival and is predictive of sentinel lymph node (SLN) positivity in some cancers. However, its usefulness as a prognostic biomarker for cutaneous squamous cell carcinoma (cSCC) has not been fully investigated. Objective Our objective was to investigate the relationship between the NLR and the disease-specific survival and SLN positivity in patients with cSCC. Methods In this single-center retrospective case series, we analyzed patients with cSCC who underwent blood tests prior to the initiation of treatment at our oncology hospital. The relationship between the patients’ clinical characteristics (including the NLR) and the disease-specific survival and SLN positivity was evaluated using univariate and multivariate analyses. Results An elevated NLR was an independent prognostic factor for poor disease-specific survival and a predictive factor for SLN positivity. Limitations Limitations include the small number of participants and selection bias due to the large proportion of high-risk cases in our patient population. Conclusion NLR is a useful biomarker in cSCC because it is simple to measure and can predict prognosis.

Aim: This study aimed to access the efficacy of plasma small nucleolar RNAs in early diagnosis of non-small-cell lung cancer (NSCLC). Methods: SNORD83A was selected based on databases and further verified in 48 paired formalin-fixed, paraffin-embedded tissues, as well as in plasma from 150 NSCLC patients and 150 healthy donors. The diagnostic efficiency of plasma SNORD83A, as well as in combination with carcinoembryonic antigen, was determined by receiver operating characteristic analysis. Results: SNORD83A was significantly increased not only in tissues but also in plasma from NSCLC patients compared with those from healthy donors. Plasma SNORD83A was able to act as a diagnostic biomarker for NSCLC. The diagnostic efficiency of carcinoembryonic antigen was also significantly elevated for early-stage NSCLC when combined with SNORD83A. Conclusion: SNORD83A can serve as a diagnostic biomarker for NSCLC.

Background: Circular RNAs (circRNAs) have been identified to be involved in a variety of human diseases such as cancers, cardiovascular diseases, and autoimmune diseases. In recent years, the role of circRNAs in the development of kidney diseases in nephrology has been gradually recognized. Objective: We updated and described the current status of circRNAs in kidney diseases in nephrology. We particularly focused on the roles and mechanisms of circRNAs in systemic lupus erythematosus and lupus nephritis. Methods: We summarized recent reports published on PubMed, Web of Science, Scopus, Scielo databases using keywords circRNAs, kidney diseases or renal diseases, or systemic lupus erythematosus. Results: Studies of circRNAs in certain kidney diseases, such as acute kidney injury, focal segmental glomerulosclerosis, idiopathic membranous nephropathy, IgA nephropathy, diabetic nephropathy, hypertensive renal damage, and particular lupus nephritis address the function and pathogenesis of circRNAs. Mechanisms of circRNAs in the above human kidney diseases so far have focused on the role of sponging microRNAs and regulating the expression of target genes. Moreover, circRNAs have been detected in blood, urine, and kidney tissue samples. These results suggest that circRNAs can serve as biomarkers for the diagnosis and monitoring of the progression of kidney diseases. Conclusion: CircRNAs play important roles in the pathogenesis, diagnosis, and treatment of kidney diseases emphasizing lupus nephritis in nephrology.

Objectives: Fetal growth restriction is associated with chronic fetal hypoxia, poor perinatal outcome and increased perinatal mortality. There are no reliable methods to detect cell damage in the central nervous system (CNS) in these patients. The findings of increased an acidic calcium-binding protein (S100B) concentration in biological fluids of infants after brain injury have supported the use of S100B as a biochemical marker of CNS damage. The purpose of the study was to assess blood S100B concentrations in small for gestational age (SGA) and appropriate for gestational age (AGA) newborns and to evaluate the usefulness of S100B for early detection of hypoxia. Material and methods: The investigation was carried out between November 2011 and April 2014. Serum S100B protein level was assessed in cord blood collected from newborns after birth. Medical records of mothers of neonates studied were reviewed for pregnancy induced hypertension (PIH), preeclampsia, maternal smoking during pregnancy and abnormalities in umbilical artery (UA) Doppler ultrasound examination. Results: The study was carried out in 88 SGA neonates and 80 AGA neonates. The median value of S100B protein concentration in the SGA study group was significantly higher than in AGA controls (p < 0.001). Cord blood serum S100B concentration in SGA neonates with prenatal normal UA Doppler ultrasound findings (n = 32) did not differ from that SGA neonates with abnormal prenatal UA Doppler findings (n = 25) (p = 0.74), but was significantly higher than in AGA newborns (p < 0.001). Conclusions : Elevated S100B protein levels in cord blood collected from SGA newborns may be helpful in detecting infants at higher risk of postnatal neurologic disturbances at an early stage.

Neurodegenerative processes in the brain are reflected by structural retinal changes. As a possible biomarker of cognitive state in prodromal α-synucleinopathies, we compared melanopsin-mediated post-illumination pupil response (PIPR) with cognition (CERAD-plus) in 69 patients with isolated REM-sleep behavior disorder. PIPR was significantly correlated with cognitive domains, especially executive functioning (r = 0.417, p

BACKGROUND: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat.OBJECTIVES: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort.METHODS: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors.RESULTS: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned.CONCLUSIONS: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.

Background: Colorectal cancer (CRC) is an important global burden, and the discovery of biomarkers for screening and monitoring is a current challenge. The present study aimed to determine the serum concentration of ROBO4 and CLEC14A in CRC patients and assess the clinical value of these diagnostic and progression biomarkers in CRC.Methods: Serum samples were collected from 32 patients with operable colorectal cancer and from 16 healthy individuals. Blood serum of CRC patients were tested at two time points (before and after surgery). Serum concentration of ROBO4 and CLEC14A were measured using ELISA tests.Results: The serum concentrations of ROBO4 and CLEC14A were significantly higher in CRC patients than non-cancer controls; the concentrations were already higher in TNM stage I + II CRC patients. The sensitivitiy and specificity of ROBO4 and CLEC14A in distiguishing cancer patients form controls ranged from 71.9–100% and from 84.5–100%, respectively. The serum ROBO4 concentration was associated with the TNM stage, depth of invasion, and lymph node and distant metastases. No significant relationship was observed between the CLEC14A concentration and the tumor site or the N and M stages. The level of ROBO4 was statistically lower 3 months after the surgery, compared to the level noted prior to the operation. The concentration of CLEC14A decreased in the postoperative period, compared to preoperative one; however, the decline was not statistically significant.Conclusion: Our preliminary study has provided evidence that ROOB4 and CLEC14A seem to be suitable biomarkers for clinical diagnostic purposes. However, ROOB4 appears to be more appropriate for assessment of CRC progression.

Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. Methods: Three separate TMA sets were built that differ by purpose and disease state. Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.

Immune effector cell (IEC) therapies have revolutionized our approach to relapsed B-cell malignancies, and interest in the investigational use of IECs is rapidly expanding into other diseases. Current challenges in the analysis of IEC therapies include small sample sizes, limited access to clinical trials and a paucity of predictive biomarkers of efficacy and toxicity associated with IEC therapies. Retrospective and prospective multi-center cell therapy trials can assist in overcoming these barriers through harmonization of clinical endpoints and correlative assays for immune monitoring, allowing additional cross-trial analysis to identify biomarkers of failure and success. The Consortium for Pediatric Cellular Immunotherapy (CPCI) offers a unique platform to address the aforementioned challenges by delivering cutting-edge cell and gene therapies for children through multi-center clinical trials. Here the authors discuss some of the important pre-analytic variables, such as biospecimen collection and initial processing procedures, that affect biomarker assays commonly used in IEC trials across participating CPCI sites. The authors review the recent literature and provide data to support recommendations for alignment and standardization of practices that can affect flow cytometry assays measuring immune effector function as well as interpretation of cytokine/chemokine data. The authors also identify critical gaps that often make parallel comparisons between trials difficult or impossible.

PURPOSE Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. MATERIALS AND METHODS Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre–CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. RESULTS We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type ( P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. CONCLUSION TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.

Background Inflammatory responses in patients with active rheumatoid arthritis (RA) may lead to the current serum and synovial fluid biomarkers that misidentify chronic periprosthetic joint infection (PJI). We sought to investigate the expression of serum and synovial biomarkers in patients with active RA and to calculate thresholds for valuable biomarkers that distinguish between chronic PJI and active RA. Methods This prospective study was initiated to enroll 70 patients undergoing revision arthroplasty from January 2019 to January 2021, and 30 patients with active RA cumulative knee from August 2020 to March 2021. The Musculoskeletal Infection Society definition of PJI was utilized for the classification of cases as aseptic or infected. Serum d -dimer, erythrocyte sedimentation rate, C-reactive protein, and interleukin-6 (IL-6), as well as synovial IL-6, percentage of polymorphonuclear neutrophils, and CD64 index level were measured preoperatively. Results An increase in biomarker concentrations were observed in group C (active RA). Synovial fluid CD64 index exhibited good discriminatory power between group B (chronic PJI) and group C with an area under curve of 0.930. For the diagnosis of chronic PJI in the presence of active RA, the optimal threshold value of synovial CD64 index was 0.87, with a sensitivity of 82.86% and a specificity of 93.33%. Conclusion Current serum biomarkers (erythrocyte sedimentation rate, C-reactive protein, IL-6, and d -dimer) did not apply to the diagnosis of suspected PJI with active RA. Fortunately, satisfactory results can be achieved by adjusting the threshold of synovial fluid biomarkers.

Background Immune checkpoint inhibitors (ICIs) have shown numerous clinical benefits in multiple cancer types, but good predictive biomarkers are severely lacking. Although increasing evidence has linked Hedgehog (Hh) signaling pathway with tumor development, a systematic investigation for its potential as a biomarker remains elusive. Methods We collected and analyzed the transcriptional data and clinical outcomes of diverse cancers from the Cancer Genome Atlas and four published ICI datasets. Hh activity was estimated by conducting a single‐sample gene‐set enrichment analysis (ssGSEA) for the Hh‐related genes and calculating the ssGSEA score in each tumor sample. Results Our findings suggest that tumors with high Hh activity displayed multiple immunosuppressive characteristics, including lack of anti‐tumor response pathways, downregulation of immune effectors, enrichment of immunosuppressive cells and chemokines, and activation of immunosuppressive signaling. Notably, patients in the non‐response group had enriched Hh activity and showed worse overall survival (OS; pooled HR = 1.50, 95% CI = 1.02–2.21, p = 0.039). In the subgroup of high programmed cell death ligand 1 (PD‐L1) expression, patients who harbored high Hh activity displayed a dramatically lower response rate to ICIs and a strikingly worse OS (pooled HR = 2.89, 95% CI = 1.53–5.49, p

Bladder cancer is the most common malignant tumours with high morbidity, mortality and recurrence. However, currently developed detection methods for bladder cancer-associated urine biomarkers are hindered by their extremely low abundance. Hence, the exploration of a highly sensitive and selective approach for the detection of trace bladder cancer-associated biomarkers in human urine is of vital importance for the diagnosis of bladder cancer. Herein, we developed a highly reliable indium gallium zinc oxide field effect transistor (IGZO FET) biosensor for the detection of bladder cancer-related biomarker microRNA. The single-stranded DNA-functionalized IGZO FET biosensors exhibit high sensing reproducibility and stability with an ultralow detection limit of 19.8 amol/L. The device could also be used for quantitative detection of trace microRNA in human urine samples and can effectively distinguish bladder cancer patients from healthy donors. The development of high performance IGZO FET biosensors presents new opportunities for the achievement of early-stage diagnosis of bladder cancer.

As a biomarker for liver disease, bilirubin has been utilized in prognostic scoring systems for cirrhosis. While laboratory-based methods are used to determine bilirubin levels in clinical settings, they do not readily lend themselves to applications outside of hospitals. Consequently, bilirubin monitoring for cirrhotic patients is often performed only intermittently; thus, episodes requiring clinical interventions could be missed. This work investigates the feasibility of measuring bilirubin concentration in whole porcine blood samples using dual-wavelength transmission measurement. A compact and low-cost dual-wavelength transmission measurement setup is developed and optimized to measure whole blood bilirubin concentrations. Using small volumes of whole porcine blood (72 µL), we measured the bilirubin concentration within a range corresponding to healthy individuals and cirrhotic patients (1.2-30 mg/dL). We demonstrate that bilirubin levels can be estimated with a positive correlation (R-square0.95) and an accuracy of ±1.7 mg/dL, with higher reliability in cirrhotic bilirubin concentrations (4 mg/dL) - critical for high-risk patients. The optical and electronic components utilized are economical and can be readily integrated into a miniature, low-cost, and user-friendly system. This could provide a pathway for point-of-care monitoring of blood bilirubin outside of medical facilities (e.g., patient's home).

BACKGROUND Although endoscopy is the gold standard to assess disease activity and infliximab efficacy in inflammatory bowel disease (IBD), the invasive, costly, and time-consuming procedure limits its routine applications. We aimed to investigate the clinical value of serum oncostatin M (OSM) as a surrogate biomarker. METHODS Fifty healthy controls, 34 non-IBD patients, and 189 IBD patients who were pre-infliximab treatment (n = 122) or in infliximab maintenance (n = 67) were enrolled. A chemiluminescence immunoassay (CLIA) was constructed to quantify serum OSM concentrations. Receiver operator characteristic (ROC) curve analysis was used to evaluate the performance of blood biomarkers for IBD management. RESULTS The methodology of CLIA exhibited great analytical performance with a wide linear range of 31.25-25000 pg/mL, a low detection limit of 23.2 pg/mL, acceptable precision, and applicable accuracy. Patients with IBD (121.5 [43.3-249.4] pg/mL, p

To investigate the prognostic value of dual-energy CT (DECT) based radiomics to predict disease-free survival (DFS) and overall survival (OS) for patients with advanced gastric cancer (AGC) after neoadjuvant chemotherapy (NAC).From January 2014 to December 2018, a total of 156 AGC patients were enrolled and randomly allocated into a training cohort and a testing cohort at a ratio of 2:1. Volume of interest of primary tumor was delineated on eight image series. Four feature sets derived from pre-NAC and delta radiomics were generated for each survival arm. Random survival forest was used for generating the optimal radiomics signature (RS). Statistical metrics for model evaluation included Harrell's concordance index (C-index) and the average cumulative/dynamic AUC throughout follow-up. A clinical model and a combined Rad-clinical model were built for comparison.The pre-IU (derived from iodine uptake images before NAC) RS performed best for DFS and OS in the testing cohort (C-indices, 0.784 and 0.698; the average cumulative/dynamic AUCs, 0.80 and 0.77). When compared with the clinical model, the radiomics model had significantly higher C-index to predict DFS in the testing cohort (0.784 vs. 0.635, p 0.001), but no statistical difference was found for OS (0.698 vs. 0.680, p = 0.473). The combined Rad-clinical models showed improved performance in the testing cohort, with C-indices of 0.810 and 0.710 for DFS and OS, respectively.DECT-derived radiomics serves as a promising non-invasive biomarker to predict survival for AGC patients after NAC, providing an opportunity for transforming proper treatment.

A common clinical phenotype of several neurodegenerative and systemic disorders including Alzheimer’s disease and atherosclerosis is the abnormal accumulation of extracellular material, which interferes with routine cellular functions. Similarly, patients with age-related macular degeneration (AMD), the leading cause of vision loss among the aged population, present with extracellular lipid- and protein-filled basal deposits in the back of the eye. While the exact mechanism of growth and formation of these deposits is poorly understood, much has been learned from investigating their composition, providing critical insights into AMD pathogenesis, prevention, and therapeutics. We identified human osteopontin (OPN), a phosphoprotein expressed in a variety of tissues in the body, as a newly discovered component of basal deposits in AMD patients, with a distinctive punctate staining pattern. OPN expression within these lesions, which are associated with AMD disease progression, were found to co-localize with abnormal calcium deposition. Additionally, OPN puncta colocalized with an AMD risk-associated complement pathway protein, but not with apolipoprotein E or vitronectin, two other well-established basal deposit components. Mechanistically, we found that retinal pigment epithelial cells, cells vulnerable in AMD, will secrete OPN into the extracellular space, under oxidative stress conditions, supporting OPN biosynthesis locally within the outer retina. Finally, we report that OPN levels in plasma of aged (non-AMD) human donors were significantly higher than levels in young (non-AMD) donors, but were not significantly different from donors with the different clinical subtypes of AMD. Collectively, our study defines the expression pattern of OPN in the posterior pole as a function of disease, and its local expression as a potential histopathologic biomarker of AMD.

Biomarker research has investigated the neurobiological basis for individual differences in liability to psychosis. However, few biomarkers for psychosis have been consistently found to be useful. This paper reviews several previous approaches to identify putative biomarkers of liability to psychosis, and then highlights the lessons that we have learned. We argue that limiting our research to clinical patients at the extreme of the psychosis continuum would likely obscure our knowledge as to how a minority of the general population would develop psychosis. Research on putative neurobiological origins of inter-individual differences in personality traits may be useful in mapping the biomarkers of psychosis. To identify biomarkers applicable to the general population, we advocate the transdiagnostic and psychosis continuum approach. We also advocate the use of multivariate analyses and computational modelling to tackle complex multi-modal datasets. More research should be conducted to study intra-individual variations over different ranges of timescale.

Purpose: Immunotherapy offers a second-line option for patients with metastatic urothelial carcinoma (mUC) who failed standard therapy, but the biomarkers for predicting response remain to be explored. This study aims to evaluate the safety, efficacy, and correlative biomarker of toripalimab in patients with previously treated mUC. Patients and Methods: Patients with mUC received toripalimab 3 mg/kg Q2W. Clinical response was assessed every 8 weeks by an independent review committee per RECIST v1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and other biomarkers were evaluated. Results: Among the intention-to-treat population (n = 151), 85% of the patients experienced treatment-related adverse event (TRAE) and 20% experienced grade 3 and above TRAE. The objective response rate (ORR) was 26% with a disease control rate (DCR) of 45%. The median duration of response, progression-free survival (PFS), and overall survival (OS) were 19.7 months [95% confidence interval (CI): 13.9–not estimable], 2.3 months (95% CI, 1.8–3.6), and 14.4 months (95% CI, 9.3–23.1), respectively. Both PD-L1+ and TMB-high (10 mutations/Mb as the cutoff) patients had better ORR than PD-L1− patients (42% vs. 17%, P = 0.002) and TMB-low patients (48% vs. 22%, P = 0.014), respectively. The TMB-high group also showed better PFS (12.9 vs. 1.8 months, P < 0.001) and OS (not reached versus 10.0 months, P = 0.018) than the TMB-low group. Conclusions: Toripalimab has demonstrated encouraging clinical activity in the second-line treatment of mUC with a manageable safety profile. PD-L1 expression and TMB were two independent biomarkers in the study.

Here we review the paradigm-change from one-size-fits-all psychiatry to more personalized-psychiatry, where we distinguish between 'precision psychiatry' and 'stratified psychiatry'. Using examples in Depression and ADHD we argue that stratified psychiatry, using biomarkers to facilitate patients to best 'on-label' treatments, is a more realistic future for implementing biomarkers in clinical practice.

Whether plasma serotonin (5-HT) levels could be a biomarker for postpartum depression (PPD) diagnosis is under dispute.A total of 979 of pregnant women without antenatal depression at the time of delivery (TD) were enrolled and followed up at six weeks postpartum (SWP) in Changsha, China. The odds ratio (OR) and 95% confidence interval (CI) for plasma 5-HT level at TD, at SWP, changes in 5-HT, and risk of PPD and deterioration in EPDS scores at SWP were estimated by Logistic regressions. Restricted cubic spline (RCS) functions were also used to assess the dose-response relationships.The 6-week cumulative incidence of PPD was 12.05% (95%CI:10.08%, 14.26%). The average level of plasma 5-HT changed from 223.65 ± 131.47 ng/ml at TD to 216.43 ± 122.73 ng/ml at SWP, with an average change of -7.22 ± 96.54 ng/ml. Plasma 5-HT at TD was negatively correlated with EPDS score at TD and SWP (p 0.05), as was the correlation between 5-HT at SWP and EPDS scores at SWP (p = 0.038). However, the changes in 5-HT were not associated with the EPDS score at SWP (p = 0.346). Neither plasma 5-HT level at TD nor changes in 5-HT was associated with PPD at SWP or deterioration in EPDS scores (p 0.05). Plasma 5-HT at delivery had insignificant discriminatory power for diagnosing PPD and prediction of deterioration in EPDS scores (p ≥ 0.05).Plasma 5-HT level at delivery was associated with EPDS score at delivery and SWP, but not with PPD at SWP suggesting that plasma 5-HT is not suitable as PPD diagnostic biomarker.

Donor-derived cell-free DNA (dd-cfDNA) has been evaluated as a rejection marker in organ transplantation. This study sought to assess the utility of dd-cfDNA to diagnose graft injury in liver transplant recipients (LTR) and as a predictive biomarker prior to different causes of graft dysfunction. Plasma from single and multicenter LTR cohorts was analyzed for dd-cfDNA. Phenotypes of treated biopsy-proven acute rejection (AR, N = 57), normal function (TX, N = 94), and acute dysfunction no rejection (ADNR; N = 68) were divided into training and test sets. In the training set, dd-cfDNA was significantly different between AR versus TX (AUC 0.95, 5.3% cutoff) and AR versus ADNR (AUC 0.71, 20.4% cutoff). Using these cutoffs in the test set, the accuracy and NPV were 87% and 100% (AR vs. TX) and 66.7% and 87.8% (AR vs. ADNR). Blood samples collected serially from LTR demonstrated incremental elevations in dd-cfDNA prior to the onset of graft dysfunction (AR > ADNR), but not in TX. Dd-cfDNA also decreased following treatment of rejection. In conclusion, the serial elevation of dd-cfDNA identifies pre-clinical graft injury in the context of normal liver function tests and is greatest in rejection. This biomarker may help detect early signs of graft injury and rejection to inform LTR management strategies.

There has been strong evidence of myocardial injury in coronavirus disease 2019 (COVID-19) patients with significantly elevated serum cardiac troponin (cTn). While the exact mechanism of injury is unclear, possible suggested pathological mechanisms of injury are discussed. These include increased susceptibility of the myocardium and endothelium to viral invasion, underlying hyperinflammatory state and subsequent cytokine storm, a hypercoagulable and prothrombotic state, and indirect myocardial injury due to hypoxemia. As a result of these pathological mechanisms in COVID-19 patients, cTn may be elevated largely due to myocarditis, microangiopathy or myocardial infarction. The utility of cTn as a biomarker for measuring myocardial injury in these patients and assessing its ability as a prognostic factor for clinical outcome is also discussed.